Vasoproliferative disorder of the retina occurring principally in new born preterm infants.
M/C cause of preventable childhood blindness worldwide
History:
Retinopathy of prematurity (ROP) used to be called as retrolental fibroplasia (RLF) in 1940s. RLF was the term first coined in the year 1942 by Terry and was defined as a progressive disorder seen exclusively in premature infants of low birth weight, where in a fibrous tissue is formed behind the lens, resulting in blindness and severe visual impairment. When it was first described this disease was not commonly seen, and hence had little interest but 10 years later it became a major problem to all paediatricians and ophthalmologists. It now affects thousands of children worldwide.
Epidemiology
Recent estimates show that 32,000 infants became blind or visually impaired from ROP every year world-wide, being a far higher estimate that 10 years ago. Most of the ROP-blind infants were born in countries in Asia. | Blencowe H, Lawn JE, Vazquez T, Fielder A, Gilbert C. Preterm-associated visual impairment and estimates of Retinopathy of Prematurity at regional and global levels for 2010. Pediatr Res. 2013 Dec; 74 Suppl 1:35-49. doi: 10.1038/pr.2013.205. Review.
Etiopathogenesis
High supplemental oxygen therapy
Primary cause of hypoxia
Schematic representation of IGF-I/VEGF control of blood vessel development in ROP. (A) In utero, (B) Premature birth, (C) Retinal maturation, (D) Retinal neovascularization. Nl: normal | Chen, J., Smith, L.E.H. Retinopathy of prematurity. Angiogenesis 10, 133–140 (2007). https://doi.org/10.1007/s10456-007-9066-0
3 phases of progression:
ROP can be viewed as an arrest of normal retinal neuronal and vascular development in the preterm infant, with ultimately pathological compensatory mechanisms that result in aberrant vascularisation of the retina.
Prephase: Antenatal sensitisation via inflammation
Phase 1 | Oxygen toxicity: Hyperoxia leads to suppression of oxygen-regulated angiogenic growth factors, particularly erythropoietin and vascular endothelial growth factor (VEGF), which in turn causes both cessation of retinal vessel growth and loss of some existing retinal vessels
Phase 2 | Hypoxia-mediated vasoproliferation: Proliferation of blood vessels largely in response to hypoxia-driven increases in VEGF and erythropoietin
Progression of retinopathy of prematurity: (A) Oxygen tension is low in utero and vascular growth is normal. (B) Phase 1: after birth until roughly 30 weeks postmenstrual age, retinal vascularisation is inhibited because of hyperoxia and loss of the nutrients and growth factors provided at the maternal–fetal interface. Blood-vessel growth stops and as the retina matures and metabolic demand increases, hypoxia results. (C) Phase 2: the hypoxic retina stimulates expression of the oxygen-regulated factors such as erythropoietin (EPO) and vascular endothelial growth factor (VEGF), which stimulate retinal neovascularisation. Insulin-like growth factor 1 (IGF-1) concentrations increase slowly from low concentrations after preterm birth to concentrations high enough to allow activation of VEGF pathways. (D) Resolution of retinopathy might be achieved through prevention of phase 1 by increasing IGF-1 to in-utero concentrations and by limiting oxygen to prevent suppression of VEGF; alternatively, VEGF can be suppressed in phase 2 after neovascularisation with laser therapy or an antibody. | EPO=erythropoietin. ω-3 PUFA=ω-3 polyunsaturated fatty acids. | Smith LE. Through the eyes of a child: understanding retinopathy through ROP the Friedenwald lecture. Invest Ophthalmol Vis Sci. 2008;49:5177–82.
Major risk factors:
Low gestational age
Low birthweight for gestational age
Other risk factors:
Hyperglycaemia, insulin, and nutrition
Bacterial and fungal sepsis
Infection, inflammation, and retinopathy of prematurity: Exposure to infection and inflammation seems to modify risk of retinopathy of prematurity, especially before (prephase) and a few weeks after birth (phase 2), when oxygen concentrations are relatively low compared with phase 1 (immediately after birth). Whereas prenatal inflammation seems to exert a sensitising effect without directly increasing risk, postnatal infection and inflammation are associated with an increased risk, perhaps most prominently in phase 2. | Lee J, Dammann O. Perinatal infection, inflammation, and retinopathy of prematurity. Semin Fetal Neonatal Med. 2012;17:26–29.
Associated neonatal morbidities:
Neurological dysfunction
Poor brain growth
Patent ductus arteriosus (PDA)
Necrotising enterocolitis (NEC)
Intraventricular haemorrhage (IVH)
Bronchopulmonary dysplasia
International Classification of Retinopathy of Prematurity:
Retina is divided into three zones and the extent or severity of disease in these zones is classified as stages
Stage 1: Thin demarcation line between vascularised and non-vascularised retina
Stage 2: Ridge
Stage 3: Extraretinal fibrovascular proliferation
Stage 4: Part retinal detachment
Stage 5: Total retinal detachment
Zones and stages of retinopathy of prematurity: The retina is divided into three zones (A, diagram shows right eye) and the extent or severity of retinopathy in these zones is classified as stages (B). Stage 1 is characterised by a thin demarcation line between vascularised and non-vascularised retina, stage 2 by a ridge, stage 3 by extraretinal fibrovascular proliferation, stage 4 by part retinal detachment, and stage 5 by total retinal detachment. In stage 3, extraretinal neovascularisation can become severe enough to cause retinal detachment (stages 4–5), which usually leads to blindness. | Hellström, A., Smith, L. E., & Dammann, O. (2013). Retinopathy of prematurity. Lancet (London, England), 382(9902), 1445–1457. https://doi.org/10.1016/S0140-6736(13)60178-6 | Part B is courtesy of Lisa Hård.
Plus disease:
Presence of increased dilation and tortuosity of posterior vessels; Ominous sign of progressive disease.
Plus disease: Compared with a normal retina (A), plus disease (B) is characterised by venous dilation and increased arterial tortuosity of posterior vessels. | International Committee for the Classification of Retinopathy of Prematurity. The International Classification of Retinopathy of Prematurity revisited. Arch Ophthalmol. 2005;123:991–99.
Threshold disease:
Defined as disease that has a 50% likelihood of progressing to retinal detachment.
Threshold disease is considered to be present when stage 3 ROP is present in either zone I or zone II, with at least 5 continuous or 8 total clock hours of disease, and the presence of plus disease.
Aggressive posterior retinopathy of prematurity (AP-ROP):
Severe and rare form of ROP characterized by fast progression to an advanced stage with flat neovascularization in zone 1 or zone 2
Presentation
The Calgary Guide | http://calgaryguide.ucalgary.ca/
Diagnosis
Screening of high-risk newborns:
Done in infants with major risk factors between 4-6 weeks of postnatal age
Low gestational age
Low birthweight for gestational age
Predictive factors for ROP progression:
Postnatal weight gain
Serum insulin-like growth factor 1 (IGF-1) levels
Quantifiable vessel changes in the retina
Mansukhani, S. (n.d.). Topics on Retinopathy Of Prematurity | Diseases and Conditions | Pediatric Oncall. Retrieved December 24, 2021, from https://www.pediatriconcall.com/articles/pediatric-ophthalmology/retinopathy-of-prematurity/retinopathy-of-prematurity-treatment
Management
Pathogenesis and Therapy of Retinopathy of Prematurity (ROP): Phases 1 and 2 of ROP are associated with different levels of vascular endothelial growth factor (VEGF), oxygen, and neovascular activity. ROP stages 0 to 5 are shown, as are the outcomes, when therapy is successful, of cryotherapy, laser therapy, and intravitreal bevacizumab. Cryotherapy involves scarring of the full ocular thickness, laser therapy scarring of the retinal thickness, and intravitreal bevacizumab scarring with a needle near the limbus. Also shown are the postmenstrual ages at which infants are at high risk for ROP, the appropriate postmenstrual age for the first ocular screening examination for ROP, and the mean postmenstrual ages at the onset of aggressive posterior ROP (APROP) (type 2 ROP) and stages 1, 2, and 3 (type 1 ROP). | Mintz-Hittner, H. A., Kennedy, K. A., & Chuang, A. Z. (2011). Efficacy of Intravitreal Bevacizumab for Stage 3+ Retinopathy of Prematurity. New England Journal of Medicine, 364(7), 603–615. https://doi.org/10.1056/NEJMoa1007374
Cryotherapy:
Treatment of the avascular retina using of a cryoprobe in order to reduce unfavorable outcomes of ROP like retinal folds and retinal detachment
Indirect laser photocoagulation
Laser ablation covers the relatively hypoxic retina into anoxic, thereby reducing stimulus for new vessel formation and disease progression
Directly block the effects of VEGF, and a single intravitreal injection is less time consuming and less expensive as compared to lasers
Intravitreal bevacizumab
Vascular endothelial growth factor/vascular endothelial growth factor (VEGF) receptor pathways involved in angiogenesis and the targets of VEGF (anti-VEGF agents): bevacizumab, ranibizumab, and aflibercept. | Arima, M., Fujii, Y., & Sonoda, K.-H. (2021). Translational Research in Retinopathy of Prematurity: From Bedside to Bench and Back Again. Journal of Clinical Medicine, 10(2), 331. https://doi.org/10.3390/jcm10020331
Surgical management:
Reserved for advanced stages of ROP (stages 4 and 5).
Stage 4:
Lens sparing vitrectomy
Scleral buckling
Stage 5:
Vitrectomy with lensectomy
Open sky vitrectomy
Fundus Photographs and Fluorescein Angiograms of Retinas in Study Infants with Stage 3+ Retinopathy of Prematurity in Zone I, before and after Treatment: Panels A and B show the left retina of an infant before conventional laser therapy (at approximately 2 months of age, or 33.1 weeks’ postmenstrual age) and after therapy (at 13 months’ postmenstrual age), respectively. The infant was born at 24 weeks’ gestational age, with a birth weight of 760 g. The post-treatment photograph shows destruction of the full thickness of the peripheral retina, with only choroidal vessels (not retinal vessels) visible in the lasered area. Panels C and D show the left retina in another infant before intravitreal bevacizumab therapy (at approximately 3 months of age, or 35.6 weeks’ postmenstrual age) and after therapy (at 13 months’ postmenstrual age), respectively. The infant was born at 23 weeks’ gestational age, with a birth weight of 495 g. The post-treatment photograph shows continued vascularization of the peripheral retina. In all four panels, black arrows indicate identical retinal points for comparison before and after treatment, and thin white arrows indicate the extent of vascularization at each time point; the wide white arrows in Panel D indicate the extent of vascularization at the time of treatment with bevacizumab. | Mintz-Hittner, H. A., Kennedy, K. A., & Chuang, A. Z. (2011). Efficacy of Intravitreal Bevacizumab for Stage 3+ Retinopathy of Prematurity. New England Journal of Medicine, 364(7), 603–615. https://doi.org/10.1056/NEJMoa1007374
